Environmental factors, including chemical agents, may play an important etiologic role in human colonic carcinogenesis. Studies from our laboratory have recently demonstrated that nitrosamines, compounds with both oncogenic and cytotoxic potential, are agonists of guanosine 3'5( monophosphate (cGMP) in normal human and rat colonic mucosa and in several other tissues from the rat. Of the nitrosamines tested to date, n-methyl-n-nitro-n-nitrosoguanidine (MNNG) has proved the most potent agonist of cGMP. At a concentration of 1 mM,MNNG increases cGMP 12-fold in human and 21-fold in rat colonic mucosa. MNNG and other nitrosamines increase the cGMP content of colonic mucosa in the absence of extracellular Ca2 ion. Moreover, these same agents stimulate guanylate cyclase activity when added directly to tissue homogenates. In both respects, the interaction of nitrosamines with the guanylate cylase-cGMP system differes from that of most currently recognized physiologic agonists of cGMP, such as cholinergic and gamma-adrenergic stimuli. The latter agents require extracellular Ca2 ion to enhance cGMP accumulation in intact cells and fail to alter guanylate cyclase activity in broken cells. It is possible that the distinct mode of activation of the guanylate cyclase system by nitrosamines circumvents available cellular feedback control mechanisms which regulate cGMP responses to physiologic agonists. cGMP has been proposed as a positive determinant for cell growth and neoplastic transformation. Several tumors, including adenocarcinoma of the human colon, are characterized by increased cGMP/cAMP molar ratios. Thus the ability of n-nitroso compounds to increase cGMP may be linked to the carcinogenic action of these compounds. The extent to which other chemical carcinogens share this property must be determined.